Our overall objective is to understand in molecular detail how genes specify the survival and identity of individual cells during development. We have discovered that mammalian counterparts of the molecules that determine the fates of the ventral nerve cord motor neurons in the nematode Caenorhabditis elegans determine hematopoietic cell fates. Mutations affecting the mammalian genes contribute to hematopoietic malignancies in children, and we envision our work in C. elegans as contributing both to understanding the specification of neuronal fates in a single tissue of an animal and to identifying essential steps in the genesis of hematopoietic malignancies that might be exploited to improve therapy. Our general approach will be to identify and characterize in detail genes that affect motor neuron identity and survival in the ventral nerve cord of C. elegans. Over the longer term in work not described in this proposal, mammalian counterparts of genes identified in C. elegans will be tested for their role in mammalian blood cell development. Thus, novel hypotheses about gene function developed through our analyses of C. elegans will direct an efficient analysis of the genes that regulate blood cell development and that contribute to hematopoietic malignancies when mutated. During the proposed grant period we will pursue the following Specific Aims: 1.) Determine whether the cell death pathway gene eg1-1 is a direct target of repression by a LIN- 39/CEH-20 heterodimer. We will use conventional transgenic approaches and comparative genomics to identify the regulatory elements in eg1-1 that control the programmed cell death pathway in the ventral nerve cord. We will test whether a Hox/Hox cofactor (LIN-39/CEH-20) heterodimer acts directly upon these elements to ensure survival of the VC neurons. 2.) Characterize four novel suppressors of programmed cell death in lin-39 mutants. In lin-39 mutants the VC motor neurons undergo programmed cell death. We have identified four novel suppressors of this defect and will determine how the VC motor neurons survive in the absence of lin-39. 3.) Identify and characterize genes that function with lin-59 to promote survival of the VC motor neurons in the C. elegans ventral nerve cord. We will use RNAi to screen 25 candidate genes and identify those that act with lin-59 to promote survival of the VC motor neurons.